TREATMENT OF COGNITIVE IMPAIRMENT WITH A CNS-PENETRANT sGC STIMULATOR

Abstract

The present invention relates to a method of treating cognitive impairment in a patient in need thereof by administering Compound (I), a stimulator of soluble guanylate cyclase (sGC) at certain dosages either alone or in combination therapy.

1 . A method of treating cognitive impairment in a patient in need thereof, by administering to said patient a total oral daily dose of between 10 mg and 15 mg of Compound I: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein the cognitive impairment is mild cognitive impairment (MCI), dementia, subclinical cognitive impairment, subjective cognitive decline (SCD) or cognitive aging. 
     
     
         3 . The method of  claim 1 , wherein the cognitive impairment is mild cognitive impairment. 
     
     
         4 . The method of  claim 1 , wherein the cognitive impairment is dementia. 
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the cognitive impairment is manifested as reduced attention, short attention span, distractibility, reduced focus or reduced processing speed. 
     
     
         6 . The method of any one of  claims 1  to  5 , wherein the patient is suffering from Alzheimer's disease (AD), vascular dementia, mixed dementia, AD with vascular pathology (ADv), cerebral infarction, cerebral ischemia, stroke, head injury, traumatic head injury, learning disabilities in children, autism, attention deficit disorder, depression, Lewy body dementia, dementia with frontal lobe degeneration, Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, cerebrodemyelination diseases, multiple sclerosis (MS), thalamic degeneration, Creutzfeldt-Jakob dementia, HIV-dementia, spinocerebellar ataxia, schizophrenia, Korsakoff psychosis, post-operative cognitive decline in the elderly, bipolar disorder, and mitochondrial disease. 
     
     
         7 . The method of any one of  claims 1  to  5 , wherein the patient is suffering from sickle cell disease. 
     
     
         8 . The method of any one of  claims 1  to  5 , wherein the patient is suffering from Alzheimer's disease (AD), vascular dementia, mixed dementia, or AD with vascular pathology (ADv). 
     
     
         9 . The method of any one of  claims 1  to  5 , wherein the patient is suffering from mitochondrial disease. 
     
     
         10 . The method of  claim 9 , wherein the mitochondria disease is selected from Alpers Disease, Autosomal Dominant Optic Atrophy (ADOA), Barth Syndrome/LIC (Lethal Infantile Cardiomyopathy), Beta-oxidation defects, Systemic Primary Carnitine Deficiency, Long Chain Fatty Acid Transport Deficiency, Carnitine Palmitoyl Transferase Deficiency, Carnitine/Acylcarnitine Translocase Deficiency, Carnitine Palmitoyl Transferase I (CPT I) Deficiency, Carnitine Palmitoyl Transferase II (CPT II) Deficiency, Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD), Long-Chain Acyl-CoA Dehydrogenase Deficiency (LCAD), Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase deficiency (LCHAD), Multiple Acyl-CoA Dehydrogenase Deficiency (MAD/Glutaric acidurioa Type II), Mitochondrial Trifunctional Protein Deficiency, Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency , Short-Chain Acyl-CoA Dehydrogenase Deficiency (SCAD), Glutaric Aciduria Type II, (SCHAD) Deficiency, Short/Medium-Chain 3-Hydroxyacyl-CoA Dehydrogenase (S/MCHAD), Medium-Chain 3-Ketoacyl-CoA Thiolase Deficiency, 2,4-Dienoyl-CoA Reductase Deficiency, Mitochondrial Enoyl CoA Reductase Protein Associated Neurodegeneration (MEPAN), Carnitine Deficiency, Creatine Deficiency Syndromes, Co-Enzyme Q10 Deficiency, Complex I, II, III, IV, V Deficiency, Chronic Progressive External Ophthalmoplegia (CPEO), Friedreich's Ataxia, Kearns-Sayre syndrome, Leukodystrophy, Leigh Disease or Syndrome, LHON, LHON Plus, Luft Disease, MELAS (Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms), Myoclonic Epilepsy with Ragged Red Fibers (MERRF), Mitochondrial Recessive Ataxia Syndrome (MIRAS), Mitochondrial Cytopathy, Mitochondrial DNA Depletion, Mitochondrial Encephalopathy, Mitochondrial Myopathy, Multiple Mitochondrial Dysfunction Syndrome, MNGIE (Myoneurogenic gastrointestinal encephalopathy), NARP (Neuropathy, ataxia, retinitis pigmentosa, and ptosis), Pearson Syndrome, Pyruvate Carboxylase Deficiency, Pyruvate Dehydrogenase Deficiency or Pyruvate Dehydrogenase Complex Deficiency (PDCD/PDH), and POLG Mutations. 
     
     
         11 . The method of  claim 10 , wherein the mitochondria disease is MELAS. 
     
     
         12 . The method of any one of  claims 1  to  11 , wherein the patient is between 65 and 100 years old or is older than 100. 
     
     
         13 . The method of  claim 12 , wherein the patient is between 65 and 90, between 65 and 80 or between 65 and 75 years old or older than 70 years old. 
     
     
         14 . The method of any one of  claims 1  to  13 , wherein the patient is administered a total oral daily dose of 15 mg of Compound I. 
     
     
         15 . The method of  claim 14 , wherein the patient is administered a single oral daily dose of 15 mg of Compound I. 
     
     
         16 . The method of  claim 14 , wherein the patient is administered two oral daily doses of 7.5 mg of Compound I. 
     
     
         17 . The method of any one of  claims 1  to  13 , wherein the patient is administered a total oral daily dose of 10 mg of compound I. 
     
     
         18 . The method of  claim 17 , wherein the patient is administered a single oral daily dose of 10 mg of Compound I. 
     
     
         19 . The method of  claim 17 , wherein the patient is administered two oral daily doses of 5 mg of Compound I. 
     
     
         20 . The method of  claim 16  or  19 , wherein the patient is administered a first dose and a second dose, wherein the first dose and the second dose are separated by a period between 5 hours and 15 hours, between 8 hours and 15 hours, or between 10 hour and 15 hours. 
     
     
         21 . The method of any one of  claims 1  to  20 , wherein treatment with Compound I results in a measurable improvement in cognition in the patient. 
     
     
         22 . The method of any one of  claims 1  to  21 , wherein treatment with Compound I results in a reduction in neuroinflammation. 
     
     
         23 . The method of  claim 21 , wherein the improvement in cognition is manifested as improvements in one or more aspects of cognition independently selected from attention, attention span, focus, reaction time to a stimulus, processing speed and a combination of these aspects thereof. 
     
     
         24 . The method of  claim 21 , wherein the improvement in cognition is manifested as improved memory or improved executive function. 
     
     
         25 . The method of  claim 21 , wherein the improvement in cognition is assessed by saccadic eye velocity (SEV) or EEG measurements. 
     
     
         26 . The method of any one of  claims 1  to  25 , wherein the method results in an increase in patient's functional capacity. 
     
     
         27 . The method of any one of  claims 1  to  25 , wherein the method does not result in symptomatic hypotension in the patient. 
     
     
         28 . The method of any one of  claims 1  to  27 , further comprising administering to the patient one or more additional therapeutic agent. 
     
     
         29 . The method of  claim 28 , wherein the additional therapeutic agent is independently selected from cholinesterase inhibitors and NMDA receptor antagonists. 
     
     
         30 . The method of  claim 29 , wherein the cholinesterase inhibitor is selected from tacrine, galantamine, donezepil, rivastigmine and a combination thereof. 
     
     
         31 . The method of  claim 29 , wherein the NMDA antagonist is memantine. 
     
     
         32 . The method of  claim 28 , wherein the additional therapeutic agent is independently selected from arginine, citrulline, and CoQ10.